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TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133561 | GEO | 2020/06/25

REPOSITORIES: GEO

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TOP2B Enzymatic Activity on Promoters and Introns Modulates Multiple Oncogenes in Human Gliomas.

Project description:PurposeThe epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors.Experimental designTo investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes.ResultsWe discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA.ConclusionsOur results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.

| S-EPMC8818263 | biostudies-literature

TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas [ATAC-seq]

Project description:We investigated the contribution of TOP2B to transcriptional modulation in gliomas given the variable expression of this helicase across tumors, and its emerging role in epigenetic regulation of transcription. We mapped the genomic location of TOP2B, and identified distinct sites of native binding and enzymatic activity across human glioma cell lines and human tumor specimens. TOP2B was active in a subset of promoters and introns, and its inhibition led to downregulation of these genes. We investigated the contribution of TOP2B to transcriptional modulation in gliomas given the variable expression of this helicase across tumors, and its emerging role in epigenetic regulation of transcription. We mapped the genomic location of TOP2B, and identified distinct sites of native binding and enzymatic activity across human glioma cell lines and human tumor specimens. TOP2B was active in a subset of promoters and introns, and its inhibition led to downregulation of these genes.

2020-06-25 | GSE134455 | GEO

TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas [RNA-seq]

2020-06-25 | GSE133557 | GEO

TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas [ChIP-seq]

2020-06-25 | GSE133263 | GEO

TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas

Project description:TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas

| PRJNA551887 | ENA

TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas [ATAC-seq]

Project description:TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas [ATAC-seq]

| PRJNA555430 | ENA

TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas [ChIP-seq]

Project description:TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas [ChIP-seq]

| PRJNA550543 | ENA

TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas [RNA-seq]

Project description:TOP2B binding and enzymatic activity on promoters and introns modulates multiple oncogenes in human gliomas [RNA-seq]

| PRJNA551885 | ENA

Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial-Mesenchymal Transition-Like Reprogramming.

Project description:Glioblastoma (GBM) is the most aggressive malignant primary brain tumour in adulthood. Despite strong research efforts current treatment options have a limited impact on glioma stem-like cells (GSCs) which contribute to GBM formation, progression and chemoresistance. Invasive growth of GSCs is in part associated with epithelial-mesenchymal-like transition (EMT), a mechanism associated with CD73 in several cancers. Here, we show that CD73 regulates the EMT activator SNAIL1 and further investigate the role of enzymatic and non-enzymatic CD73 activity in GBM progression. Reduction of CD73 protein resulted in significant suppression of GSC viability, proliferation and clonogenicity, whereas CD73 enzymatic activity exhibited negative effects only on GSC invasion involving impaired downstream adenosine (ADO) signalling. Furthermore, application of phosphodiesterase inhibitor pentoxifylline, a potent immunomodulator, effectively inhibited ZEB1 and CD73 expression and significantly decreased viability, clonogenicity, and invasion of GSC in vitro cultures. Given the involvement of adenosine and A3 adenosine receptor in GSC invasion, we investigated the effect of the pharmacological inhibition of A3AR on GSC maintenance. Direct A3AR inhibition promoted apoptotic cell death and impaired the clonogenicity of GSC cultures. Taken together, our data indicate that CD73 is an exciting novel target in GBM therapy. Moreover, pharmacological interference, resulting in disturbed ADO signalling, provides new opportunities to innovate GBM therapy.

| S-EPMC7698190 | biostudies-literature

Transcription factor binding to Caenorhabditis elegans first introns reveals lack of redundancy with gene promoters.

Project description:Gene expression is controlled through the binding of transcription factors (TFs) to regulatory genomic regions. First introns are longer than other introns in multiple eukaryotic species and are under selective constraint. Here we explore the importance of first introns in TF binding in the nematode Caenorhabditis elegans by combining computational predictions and experimentally derived TF-DNA interaction data. We found that first introns of C. elegans genes, particularly those for families enriched in long first introns, are more conserved in length, have more conserved predicted TF interactions and are bound by more TFs than other introns. We detected a significant positive correlation between first intron size and the number of TF interactions obtained from chromatin immunoprecipitation assays or determined by yeast one-hybrid assays. TFs that bind first introns are largely different from those binding promoters, suggesting that the different interactions are complementary rather than redundant. By combining first intron and promoter interactions, we found that genes that share a large fraction of TF interactions are more likely to be co-expressed than when only TF interactions with promoters are considered. Altogether, our data suggest that C. elegans gene regulation may be additive through the combined effects of multiple regulatory regions.

| S-EPMC3874175 | biostudies-literature

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